K+ homeostasis is critical for normal cardiovascular and neuromuscular function, and disturbances in K+ homeostasis (e.g., hyperkalemia) can lead to life-threatening cardiovascular events. Our long-term objective is to fully understand K+ homeostatic mechanisms. Extracellular K+ homeostasis is maintained by renal and extrarenal mechanisms. The kidneys have a remarkable capacity to regulate K+ excretion to match K+ intake. We recently studied the sensing of K+ intake by infusing K+ into rats via various routes (i.e., jugular vein, hepatic portal vein, and stomach). The results demonstrated that, when K+ enters the stomach together with a meal, there was a marked increase in plasma K+ clearance, suggesting the existence of a gut factor that increases plasma K+ clearance during dietary K+ intake. Additionally, there was an apparent increase in renal efficiency of K+ excretion, suggesting that there is a gastric-renal K+ axis. These provocative findings are limited in that plasma K+ level was not the same in the different K+ infusion groups, and, thus, renal efficiency of K+ excretion was assessed at different plasma K+ levels. In addition, we did not assess extrarenal cellular K+ uptake. We developed the K+ clamp technique for quantification of both renal K+ excretion and cellular K+ uptake at matched K+ levels under various conditions in rats. We propose to combine the K+ clamp technique with the K+ infusion experiments to follow up on our novel findings: we will test the hypothesis that there is a gut factor and identify the underlying mechanisms. Aim 1. Test the hypothesis that there is a gut factor that enhances both renal and extrarenal K+ handling during dietary K+ intake. Using the K+ clamp technique, we will attempt to establish that a gut factor is activated when K+ enters the stomach together with a meal and that it stimulates not only renal K+ excretion but also extrarenal cellular K+ uptake. We will also test whether the effect on renal K+ excretion is mediated by ROMK activation in the kidney. Aim 2. Test the hypothesis that the gut factor is activated only in the presence of meal nutrients, involving secretion of humoral factors, but not neural regulation. We will test whether the gut factor is activated by concurrent infusion of K+ and glucose into the gut and whether its effect on renal K+ excretion is mediated by a humoral factor (known or unknown) or an efferent neural pathway to the kidneys. This project will potentially establish the existence of an important, previously unknown factor, i.e., gut factor, in the maintenance of K+ homeostasis, which could be identified and studied at cellular or molecular levels by a subsequent R01 grant. PUBLIC HEALTH RELEVANCE This project will potentially establish the existence of an important, previously unknown factor (i.e., gut factor) that is activated for K+ homeostasis during dietary K+ intake. If a novel gut factor is subsequently identified, it would greatly enhance our understanding of K+ homeostatic mechanisms. In addition, there is an intriguing possibility that such a factor mediates some of the beneficial effects of increased dietary K+ intake on hypertension, stroke, and/or cardiovascular disease.